Abstract
Purpose :
The management of neovascular age-related macular degeneration (nAMD) is hindered by the need for multiple, repeat intravitreal injections of anti-VEGF agents. A method for sustained release of therapeutic agents would be highly beneficial to reduce the treatment burden for patients. We recently published a drug crystal formulation of sorafenib (SFB), which inhibits multiple receptor tyrosine kinases including VEGFR, with long-term anti-tumor and anti-angiogenic activity following a single, standalone injection. The objective of this study is to optimize drug crystal formulation of SFB for intraocular use and rigorously assess the therapeutic potential of crystalline SFB in a laser-induced choroidal neovascularization (LI-CNV) mouse model.
Methods :
Choroidal neovascularization was induced by laser on 8 to 10-week-old C57BL/6J mice. The mice were administered a single intravitreal injection of crystalline SFB (in a solution of 50% fetal mouse serum + 50% saline) 14 days prior to laser application ( n=10), with a parallel group receiving only the vehicle solution (50% FMS + 50% saline, n=10) as controls. We evaluated CNV leakage at 7- and 14-days post-laser injury using fundus fluorescein angiography (FFA). CNV lesion area was quantified 14 days after laser by isolectin-488 staining of RPE/choroid flat-mounts. To figure out the amount of SFB crystal drug left in the eye over time, we utilized protein precipitation to separate the drug from the eye and ran HPLC on the drug solution acquired to determine the amount of drug at day 14 compared to day 0.
Results :
At 7 days post-laser, the mean leakage fluorescence intensity was reduced by 40% in the crystalline SFB group compared to control, with a statistically significant reduction. At 14 days, mean leakage fluorescence intensity was reduced by 75% in the crystalline SFB group compared to control (p=0.0007). Average CNV areas on day 14 post-laser treatment were 30,052 sq. µm for the control and 21,131 sq. µm for the SFB group (p = 0.0608). HPLC analysis showed that after 14 days in the eye, 20% of the crystal remained for further drug release (p = 0.1006).
Conclusions :
Our findings indicate a therapeutic effect of our crystalline sorafenib formulation for LI-CNV, suggesting that this strategy could be used for neovascular AMD. In addition, crystalline drug delivery could be useful for other agents for the treatment of wet AMD and other retinal conditions.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.